DESCRIPTION: (Applicant's Abstract) This application is for a Mentored Clinical Scientist Development Award (MCSDA). Previously, in the laboratory of Ora Rosen, M.D. as part of my M.D.-Ph.D. training, I used biochemical and molecular techniques to dissect the mechanisms of signal transduction in a well characterized receptor system, the human insulin receptor. Last July I completed my clinical training in neurology, during which I spent some time in the laboratory of Eric Nestler, M.D., Ph.D. in the Abraham Ribicoff Research Facilities of the Yale University Department of Neurology and Psychiatry. Now, as an Assistant Professor in the Departments of Neurology and Psychiatry I seek to establish a laboratory investigating the roles of neurotrophic growth factors and their signaling pathways in the pathogenesis and treatment of neurologic and psychiatric diseases, particularly drug addiction. I have chosen to continue under the mentorship of Dr. Nestler, and within the Ribicoff Facilities, to learn the fundamentals of neuroscience, neuropharmacology, and the biological basis of drug addiction, while developing my research program. This MCSDA would greatly facilitate my development as an independent neuroscientist by supporting these training and research activities and guaranteeing that I may devote a majority of my time and effort to research. Drug addiction is one of the most prevalent, costly, and intractable personal and societal illnesses in this country. Persistent drug dependence and cravings are hallmarks of addiction and very likely represent an underlying process of drug-induced neural plasticity. The pharmacological and anatomic features of addiction have been extensively characterized in human and animal studies. Dr. Nestler and his colleagues have been at the forefront of defining the biochemical and molecular adaptations due to drugs of abuse. Dopaminergic ventral tegmental area (VTA) neurons are thought to be involved in mediating the rewarding properties of opiates, cocaine, and other drugs of abuse. Dr. Nestler's laboratory has defined a number of properties of opiates, cocaine, and other drugs of abuse. Dr. Nestler's laboratory has defined a number of persistent biochemical adaptations in the VTA, including alterations in tyrosine hydroxylase, neurofilaments, and neuron morphology. Neurotrophin infusion into the VTA can ameliorate at least some of the biochemical and behavioral changes due to drugs of abuse. Conversely, drugs of abuse may lead to VTA neuron plasticity via actions on neurotrophin signaling pathway elements. Therefore, a major goal of the research proposed in this MCSDA is to elucidate the role of neurotrophins and neurotrophin signaling pathway elements in the causes and reversal of persistent changes seen in dopaminergic VTA neurons associated with chronic exposure to drugs, using animal and cell-line models; where appropriate.